Among gastrointestinal hormones, motilin is a straight peptide consisting of 22 amino acids that is known to control gastrointestinal motility of mammals including human. Motilin receptors have been known to be predominantly localized in the upper gastrointestinal tract such as stomach and duodenum, and recently found to be also localized in the lower gastrointestinal tract such as large intestine (William et al., Am. J. Physiol., 262, G50–G55 (1992)), showing that motilin may be involved in the motility of not only the upper but also the lower gastrointestinal tract.
It was reported that patients of irritable bowel syndrome showing diarrhea conditions or patients of irritable bowel syndrome under stress show hypermotilinemia (Preston et al., Gut, 26, 1059–1064 (1985); Fukodo et al., Tohoku J. Exp. Med., 151, 373–385 (1987)), suggesting that increased blood motilin may be involved in this pathology. Other pathologies reported to be associated with hypermotilinemia include Crohn's disease, ulcerative colitis, pancreatitis, diabetes, obesity, malabsorption syndrome, bacterial diarrhea, atrophic gastritis, postgastrectomy/enterectomy, etc. Therefore, motilin receptor antagonists may potentially improve pathologies with increased blood motilin such as irritable bowel syndrome.
Recently, efforts have been made to develop and research motilin receptor antagonists, and various compounds have been reported (JP-A-7-138284, JP-A-2000-44595, etc.).
Especially, JP-A-7-138284 discloses cyclic peptide derivatives, which are used as pharmacological tools in studies of the effect of motilin on gastrointestinal motility or development and research of pharmaceuticals in this field of the art. However, their motilin antagonist activity is not sufficient and it would be desirable to develop cyclic peptide derivatives having higher activity.